High drug load acid labile pharmaceutical composition

ABSTRACT

A high drug load spheronized beadlet is provided wherein said beadlet comprises about 80% to 100% by weight of an acid labile medicament, preferably didanosine, about 0% to about 10% by weight of a disintegrant, and about 0% to about 10% by weight of a binder selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose, potassium alginate, and partially pregelatinized corn starch. A high drug load pharmaceutical composition, comprising the beadlet, with an enteric coating disposed thereon, is also provided.

RELATED APPLICATIONS

[0001] This application is a Continuation-in-Part of U.S. Ser.No.09/735,059, filed Dec. 12, 2000, which is a continuation of U.S. Ser.No. 09/408,098, filed Sep. 29, 1999, which is a continuation of U.S.Ser. No. 09/083,579 filed on May 22, 1998, each of which is incorporatedin its entirety, herein, by reference.

BACKGROUND OF THE INVENTION

[0002] 2′, 3′-dideoxyinosine, which is also known as didanosine or ddI,is an acid labile drug which will degrade in the stomach. Didanosine hasthe following structural formula.

[0003] Didanosine is known to be effective in the treatment of patientswith the HIV virus by inhibiting HIV replication. Furthermore, ddI hasbecome widely used as a component of the therapeutic cocktails fortreating AIDS.

[0004] Didanosine is generally available in a variety of oral dosages,including Chewable/Dispersible Buffered Tablets in strengths of 25, 50,100 or 150 mg of didanosine. Each tablet is buffered with calciumcarbonate and magnesium hydroxide. Didanosine tablets also containaspartame, sorbitol, microcrystalline cellulose, Polyplasdone®,mandarin-orange flavor, and magnesium stearate. Didanosine BufferedPowder for Oral Solution is supplied for oral administration insingle-dose packets containing 100, 167 or 250 mg of didanosine. Packetsof each product strength also contain a citrate-phosphate buffer(composed of dibasic sodium phosphate, sodium citrate, and citric acid)and sucrose. A didanosine Pediatric Powder for Oral Solution is alsoavailable and which is supplied for oral administration in 4- or 8-ounceglass bottles containing 2 or 4 grams of didanosine respectively, and isto be mixed with commercial antacid before oral ingestion.

[0005] With particular emphasis on the tablets, whether ingested aloneor as part of a combination (“cocktail”) therapy regimen, the currentchewable/dispersible buffered tablets are not conducive from a patientease of use standpoint. Whereas the other products which are a part ofthe AIDS therapeutic cocktail are capsules or tablets and easilyswallowed, the ddI Chewable/Dispersible Buffered Tablets must bethoroughly chewed or uniformly dispersed in water before administration.

[0006] Because ddI degrades rapidly at acidic pH, ddI, in itschewable/dispersible form and its buffered powder for oral solutionform, contains buffering agents and is administered with antacids in thepediatric powder form. However, the presence of the large quantities ofantacid components in the formulation can lead to significant GIimbalance as noted by severe diarrhea. Many patients also complain aboutchewing the large ddI tablets (a single dose is two tablets of 2.1 geach), the taste of the ddI or the time required to disperse the tabletsand the volume of fluid (4 oz) required for the dose. As the currentadult dose is 200 mg ddI, twice a day, or a single dose of 400 mg ddIdaily, a high ddI load formulation without antacid or buffers isnecessary to avoid the discomforting side effects and difficulty ofadministering the current ddI compositions.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a spheronized beadlet comprisingabout 80% to about 100% by weight of an acid labile medicament, about 0%to about 10% by weight of a disintegrant, and about 0% to about 10% byweight of a binder selected from the group consisting of sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, potassiumalginate, sodium alginate and partially pregelatinized corn starch. Thepresent invention also relates to a high drug load pharmaceuticalcomposition comprising said acid labile spheronized beadlet and anenteric coating disposed thereon. The present invention further relatesto processes for making said spheronized beadlet and high drug loadpharmaceutical composition.

[0008] The beadlets and pharmaceutical composition of the presentinvention are useful for administering a high loading of acid labilemedicament is a small total amount of pharmaceutical composition.

DETAILED DESCRIPTION

[0009] In the present invention, a spheronized beadlet is providedwherein the beadlet contains (a) a high loading, about 80-100% byweight, of an acid labile medicament such as ddI, pravastatin,erythromycin, digoxin, pancreatin, 2′, 3′-dideoxyadenosine, 2′,3′-dideoxycytosine and the like, (b) optionally one or more binders, and(c) optionally a disintegrant. Preferably, the acid labile medicament isddI.

[0010] Binders, suitable for the present invention, are those which arenon-acidic and, when utilized in small proportions, support formation ofbeadlets during spheronization. A suitable binder should also benon-acidic, and preferably alkaline, so as to minimize degradation ofthe acid labile medicament during spheronization. Typically, suitablebinders include one or more binders wherein the amount of binder presentin the core is an amount within the range of from about 0% to about 10%by weight, and preferably, about 1% by weight of the beadlet. In thepresent invention, sodium carboxymethylcellulose is the preferredbinder. Examples of other binders, which are suitable for use in thepresent invention, include partially pregelatinized corn starch (Starch1500; Colorcon, Ltd.), hydroxypropyl methylcellulose (HPMC) (Shin-EtsuChemical Co., Ltd.), potassium alginate and sodium alginate.

[0011] The spheronized beadlet of the present invention may also includeone or more disintegrants in an amount within the range from about 1% toabout 4% by weight of the beadlet. Examples of suitable disintegrantsinclude sodium starch glycolate (EXPLOTAB®; Edward Mendell Co.),cross-linked sodium carboxymethylcellulose (Ac-Di-Sol; FMC Corp), cornstarch, and cross-linked polyvinylpyrrolidone. Sodium starch glycolateis the preferred disintegrant.

[0012] In the process of the present invention of high (80-100%) potencybeadlets, containing acid labile medicaments, such as ddI, are formedusing an aqueous extrusion/spheronization methodology. No specializedequipment is required as conventional extrusion and spheronizationequipment was found to be adequate for beadlet formation. Use of anon-acidic, and preferably alkaline binder, such as sodiumcarboxymethylcellulose, and dusting during spheronization with a dryblend mixture, comprising the medicament, the optional binder, and theoptional disintegrant, provide assurance of the chemical stability ofthe medicament and maximize the drug load. The process of the presentinvention also resulted in a high (>90%) yield of beads of narrowparticle size cut.

[0013] The beadlets of the present invention may be prepared as follows.A granulation solvent, such as is typically suitable for spheronizationof an acid labile medicament, is mixed with (a) an acid labilemedicament, (b) optionally a binder, and (c) optionally a disintegrant,to form a wet mass. The preferred granulation solvent is water. Therelative proportions of the components in the wet mass are typicallyabout 80-100 parts by weight acid labile medicament, about 0 to about 10parts binder, about 0 to about 10 parts disintegrant, and about 20 toabout 36 parts granulation solvent. Preferably, the relative proportionsof the components of the wet mass containing ddI are about 95 parts ddI,1 part sodium carboxymethylcellulose, 4 parts sodium starch glycolateand about 25 parts water.

[0014] The wet mass is then extruded, for example by employing a Nica orother type extruder, to form an extrudate. The extrudate is subsequentlyspheronized using a spheronizer such as Caleva, Nica or other type, toform beadlets. During spheronization, a dry mixture containing the sameproportions of acid labile medicament, optional binder and optionaldisintegrant, as are present in the wet mass, is dusted onto theextrudate and onto the forming beadlets to absorb granulation solvent atthe surface of the extrudate and beadlets and, thus, reduce the surfacetackiness of the beadlets, thereby forming non-agglomerating beadlets.

[0015] In one embodiment, the dry mixture is prepared and then separatedinto two parts. of these parts, a first part, containing about 4% toabout 15% of the dry mixture, is set aside for use in dusting duringspheronization, while the second part is mixed with the granulationsolvent to form the wet mass which is subsequently extruded andspheronized.

[0016] Normally, drug beads are formed, through spheronization, by firstpreparing a wet mass which is extruded into threads or noodles. Thesethreads or noodles are then spun on a high-speed rotating plate whichbreaks them into small pieces and rounds the ends to make sphericalparticles by a process known as spheronization. This spheronizationgenerates centrifugal force. Under these forces, if the particles do nothave enough moisture absorbent, the moisture will be extracted out ofthe particles (drawn to the surface during spheronization), which willcause agglomeration. Typically, in the art, microcrystalline cellulose,which is a good moisture absorbent, is used as the binder to supportbead formation through spheronization. However, to adequately supportformation of non-agglomerating beads during spheronization,microcyrstalline cellulose usually constitutes more than 15% by weightto about 30% by weight of the extrudate.

[0017] In the process of the present invention, non-agglomeratingbeadlets are formed by spheronization wherein the beadlets have a highdrug loading (80-100% by weight) and a low binder loading (0-10% byweight). This is done (a) by using a medicament, optional binder,optional disintegrant mixture wherein the medicament itself, themedicament/binder mixture, or the medicament/binder/disintegrant mixtureis capable of becoming tacky upon wetting with a suitable granulationsolvent to support beadlet formation, and (b) by dusting the beadlets,while forming during spheronization, with the dry mixture of themedicament, optional binder and optional disintegrant. During thisprocess, moisture is extracted out of these particles. The dry mixtureis dusted upon the moist particles to quench the surface moisture. Thisrenders the particles relatively dry and free to move in a conventionalrope formation pattern in the spheronizer. Accordingly, formulation ofthe beadlets by spheronization progresses without beadlet agglomeration.

[0018] Optionally, the non-agglomerating beadlets are then sized throughmesh screens to obtain the desired beadlet sizes.

[0019] The non-agglomerating beadlets are then dried by suitablemethods, such as by tray drying or by fluid bed drying, to form the dryspheronized beadlets of the present invention.

[0020] A pharmaceutical composition of the present invention comprises acore, which is the dry spheronized beadlet, and an enteric coatingsurrounding said core. Typically, the core employed in thepharmaceutical composition of the present invention may be formed of abeadlet or pellet having a diameter of from about 0.5 to about 5 mm, andpreferably from about 1 to about 2 mm.

[0021] The enteric coating should provide for protection of the acidlabile medicament at a pH less than 3 (such as found in the stomach) butwill permit drug release at a pH of 4.5 or higher (such as found in theupper intestines).

[0022] As used herein “enteric coating”, comprises a polymeric material,or materials, which encases the medicament core. A suitable entericcoating, of the present invention, is one which will have no significantdissolution at pH levels below 4.5.

[0023] Further, to provide a predictable dissolution profile,corresponding to the small intestine transit time of about 3 hours, andpermit reproducible release therein, it is preferred that the entericcoating should begin to dissolve at a pH between about 4.5 and 5.5,which is within the pH range of the duodenum, and continue to dissolveat the pH range within the small intestine which is up to about 7.2 pH.Thus, the amount of enteric coating used should be such that it issubstantially dissolved during the approximate three hour transit timewithin the small intestine.

[0024] Enteric coatings, suitable for the present invention, includeenteric coating polymers known in the art, for example, hydroxypropylmethylcellulose phthalate (HPMCP-HP50, USP/NF 220824 HPMCP-HP55, USP/NFtype 200731 and HP55S; Shin Etsu Chemical), polyvinyl acetate phthalate(Coateric™; Colorcon Ltd.), polyvinyl acetate phthalate (Sureteric™;Colorcon, Ltd.), and cellulose acetate phthalate (Aquateric™; FMC Corp.)and the like.

[0025] Preferably, the enteric coating will use a methacrylic acidcopolymer. More preferably, the methacrylic acid copolymer will be anaqueous acrylic resin dispersion. Even more preferably, the entericcoating will use an anionic copolymer derived from methacrylic acid andethyl acrylate with a ratio of free carboxyl groups to the ester ofapproximately 1:1, having a mean molecular weight of approximately250,000, which is supplied as in aqueous dispersion containing 30% w/wof dry lacquer substance, (Eudragit® L30D-55; Rohm-Pharma Co., Germany).

[0026] Most enteric coating materials known in the art are acidic innature and may cause chemical degradation of an acid labile medicamentwhen in direct contact with said medicament. This is especially trueunder the high temperature and humidity conditions experienced during anaqueous enteric coating process. To minimize this acid-causeddegradation, a protective coat or subcoat is typically applied to theparticles, beadlets, pellets, etc. prior to applying an enteric coating.This protective coat physically separates the acid labile medicamentfrom the enteric coating thereby improving the stability of themedicament. Thus, in the present invention, it is most preferred thatthe enteric coating polymer will have a pH which does not causesignificant degradation of the acid labile medicament within the core,typically a pH of about 4.5 or higher and preferably a pH of about 5.0or higher.

[0027] When using an acidic enteric coating polymer in this process, thepH of said enteric coating polymer is raised by using a suitablealkalizing agent such as, for example, sodium hydroxide. The pH of theenteric coating polymer is raised to a point which is below the pHwherein the enteric integrity of the polymer could be lost. This partialacid neutralization provides a more stable composition for the acidlabile drug in the core. As a result, there is no significantincompatibility between the acid labile medicament and the entericcoating. Thus, a protective subcoat between the medicament and theenteric coating is not necessary to reduce acid degradation of the core.This process also may allow for the quicker release of the medicamentsince a subcoat layer would delay drug release and since the pH of theenteric coating will only have to be slightly raised to result in thebreakdown of the enteric coating.

[0028] In addition, the enteric coating will preferably contain aplasticizer. Examples of suitable plasticizers include triethyl citrate(Citroflex-2), triacetin, tributyl sebecate and polyethylene glycol.

[0029] Preferably, the plasticizer will be diethyl phthalate.

[0030] In the present invention, the enteric coating will have a weightratio to the core within the range of from about 5% to about 30% toprovide for release in the small intestine, but may be increased toapproximately 60% for release in the colon.

[0031] More preferably, the enteric coating will include methacrylicacid copolymer in an amount of approximately 5% -30%, and preferably 10%-20% by weight based on solids content of the enteric coating solution,and plasticizer in an amount of approximately 1% -6%, and preferably 2%-3% by weight. All of the above weights are based on total concentrationof solids in the enteric coating solution/suspension.

[0032] The dry spheronized beadlets may then be coated with an entericfilm coating suspension comprising the enteric coating polymer andoptional plasticizer, using a suitable coating system such as a fluidbed coater or other suitable coating system, and then dried. It ispreferred that during preparation of the film coating suspension, a NaOHsolution is added to the suspension until a suitable pH is obtained.

[0033] Preferably, the pharmaceutical composition of the presentinvention further comprises an anti-adherent coating disposed on theexterior of the enteric coating. Often, enteric-coated or modifiedrelease beads or particles are prepared for oral delivery of the drugsin capsule dosage form. Upon oral ingestion the capsule shell dissolvesallowing the contents in the capsule to be exposed to the gastriccontents. Due to the presence of fluids in the stomach, exposedparticles become moistened. If the moist particles do not sticktogether, they will disperse into the gastric contents and may begin toenter the duodenum based on the size distribution and other factorswhich control the gastric transit time. However, if the particles becometacky upon moistening, they may stick together as one or more lumps. Inthis case, such lumps may behave as large particles and their gastricemptying time will be variable depending upon the size and the strengthof the lumps formed. In this case, such a dosage form would not behaveas a true multiparticulate system. In order to reduce the potential forthis problem, according to the process of the present invention,enteric-coated beadlets, pellets, particles or tablets are coated with ahydrophobic material before encapsulation. The amount of hydrophobiccoating is kept to a level where it is just enough to prevent particlesticking after the capsule shell has dissolved, but not too much toretard dissolution. By this simple process, the particles behave asindividual particles, and the gastric transit time is closer to thatwhich is expected for the particle size for which the dosage form wasdesigned, thus resulting in a more predictable and less variable dosageform.

[0034] The anti-adherent (anti-agglomerant) is typically a hydrophobicmaterial such as talc, magnesium stearate or fumed silica. Talc is thepreferred anti-adherent.

[0035] The invention is particularly adapted to pharmaceuticalcompositions such as beadlets, pellets or tablets, preferably beadlets,containing ddI as the medicament. ddI will be present in an amount ofabout up to 100% of the composition in the uncoated beadlets.

[0036] The beadlets may then be filled into hard shell capsules, such asgelatin capsules of varying sizes depending on the dosage of medicamentdesired.

[0037] It is preferred that the acid labile medicament be encapsulatedwithin a capsule, or capsules, in a dose amount suitable for once dailyor twice daily administration. For administration of ddI, the once dailydosage amount is about 400 mg of ddI while the twice daily dosage amountis about 200 mg ddI per dose.

[0038] A preferred enteric coated beadlet formulation is set out below.Proportion Preferred Material Ranges Proportion CORE COMPONENTMedicament    80-100.00 95.00 Binder  0-10 1.00 Disintegrant  0-10 4.00ENTERIC COATING Polymer  5.0-30.0 10-20 Plasticizer 0.5-6.0 1.5-3.0ANTI-ADHERENT COATING Anti-adherent 0.1-4.0 0.2-0.5

[0039] The Example represents a preferred embodiment of the presentinvention. The following example further describes the materials andmethods used in carrying out the invention and is intended to be forillustrative purposes only, and is not intended to limit the scope orspirit of this invention or the claims in any way. All temperatures areexpressed in degrees Centigrade unless otherwise indicated and all meshsizes are U.S. standard ASTM.

EXAMPLE

[0040] A preferred ddI formulation in the form of enteric coatedbeadlets was prepared as described below. ddI (60 kg), sodium starchglycolate (2.523 kg) and NaCMC (0.633 kg) were placed in a PMA 300 mixerand then were mixed for 5±2 min at 200 RPM to form a dry blend. Prior tomixing, if any of the ingredients required delumping, they were passedthrough a #20 mesh stainless steel screen.

[0041] Approximately 4-15% of the dry blend, preferably 9.5%, was thenremoved and set aside for use in dusting during spheronization. Theremaining dry blend was then granulated by adding 16 kg of 20-40° C.water while mixing at 200 RPM until a suitable wet mass was achieved forextrusion. The wet mass was extruded through a suitable screen using aNica Model E140, Feeder Speed 1, Agitator Speed 1 extruder. Theextrudate was then transferred to a spheronizer system, fitted with a1.25 mm screen and radial cross hatch friction plates, and spheronizedat 300 RPM for approximately 1.5 minutes to form wet beadlets. Duringspheronization, the dry blend, which was previously set aside, was usedto dust the wet beadlets to prevent beadlet agglomeration. After theappropriate spheronization time, the product was discharged.

[0042] The spheronized wet beadlets were then gently passed through #10and #18 size mesh screens to collect {fraction (10/18)}mesh productfraction. The over 10 and under 18 sized mesh fractions were returned tothe extruder for re-extrusion and spheronization. This process wascontinued until at least 90% of the product fraction was obtained. The{fraction (10/18)}mesh product fraction was then dried using a GlattGPCG120 fluid bed dryer set at 65° C. to achieve a moisture content ofless than 3%. The dried beadlets were then screened through #10 and #20mesh screens to remove any lumps or undersized beadlets. The {fraction(10/20)}mesh product fraction dried beadlets were collected.

[0043] To prepare sufficient quantities of film coating to coat 140 kgof dried beadlets, Eudragit L-30-D 55 was filtered through a #60 meshscreen to remove any lumps present therein and then the Eudragit (101.5kg, dry weight) was mixed with 43 kg of water. The mixture wascontinuously stirred for 15 minutes. Subsequently, with continuedstirring, at 20-35° C. NaOH solution (0.15 kg NaOH, 3.75 kg water) wasadded to the vessel until a pH of 5.0±0.1 was obtained. Subsequently,with continuous stirring, diethyl phthalate (4.566 kg) was added to thevessel. Stirring continued for an additional 20 minutes.

[0044] The beadlets were then coated with 1.09 kg of coating suspensionper kg of beadlets, using a GLATT GPCG-120 with a 32″ Wurster Coater, toachieve a 16-20% w/w film coating.

[0045] Before commencing application of the film coating suspension, thebeadlets were charged into the column of the GPCG-120, fluidized with anair flow of 1900-2400 CFM, and then heated to approximately 40° C. Thecoating suspension was then sprayed onto these fluidized beadlets whileadjusting air flow or coating suspension flow to maintain temperaturebetween 32-37° C. After coating, beadlet fluidization was continued for15 minutes to permit beadlet cooling.

[0046] The weight of the talc, about 0.002 kg of talc per kg of coatedbeads, to add based on the net weight of the coated beadlets wasdetermined. The enterically coated beadlets were then placed in asuitable tumbling type blender with the talc and blended for 15±5minutes. The beadlets were then transferred to a suitable container(s)lined with two polyethylene bags and the net weight was determined.

[0047] The so formed beadlets may then be filled in to capsules orshells, such as gelatin capsules for ease of swallowing.

[0048] The so formed enteric coated ddI product was found to giveexcellent protection against gastric acid (at pH of 3) but had excellentrelease of ddI at pH's above 4.5.

1. A spheronized beadlet comprising: a) about 80% to about 100% byweight of an acid labile medicament; b) about 0% to about 10% by weightof a disintegrant; and c) about 0% to about 10% by weight of a binderselected from the group consisting of sodium carboxymethylcellulose,hydroxypropylmethylcellulose, potassium alginate, sodium alginate andpartially pregelatinized corn starch.
 2. The spheronized beadlet ofclaim 1 wherein the acid labile medicament is selected from the groupconsisting of 2′, 3′-dideoxyadenosine, 2′, 3′dideoxycytosine,pravstatin, erythromycin, digoxin and pancreatin.
 3. The spheronizedbeadlet of claim 1 wherein the acid labile medicament is 2′,3′-dideoxyinosine.
 4. The spheronized beadlet of claim 1 wherein saiddisintegrant is sodium starch glycolate, cross-linked sodiumcarboxymethylcellulose, corn starch or cross-linkedpolyvinylpyrrolidene.
 5. A pharmaceutical composition comprising a coreand an enteric coating for said core, said core comprising about 80% toabout 100% by weight of an acid labile medicament, about 0% to about 10%by weight of a disintegrant, and about 0% to about 10% by weight of abinder selected from the group consisting of sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, potassiumalginate, sodium alginate and partially pregelatinized corn starch. 6.The pharmaceutical composition of claim 5 wherein said core is in theform of a beadlet.
 7. The pharmaceutical composition of claim 5 whereinthe weight ratio of enteric coating to core is between about 0.05:1 toabout 0.6:1.
 8. The pharmaceutical composition of claim 5 wherein saidenteric coating comprises a polymer and a plasticizer.
 9. Thepharmaceutical composition of claim 8 wherein said polymer is selectedfrom the group consisting of hydroxypropylmethylcellulose phthalate,polyvinyl acetate phthalate and cellulose acetate phthalate.
 10. Thepharmaceutical composition of claim 8 wherein said polymer comprises amethacrylic acid copolymer.
 11. The pharmaceutical composition of claim10 wherein said enteric coating includes the methacrylic acid copolymerin an amount within the range of from about 5 to about 30% of the totalcomposition weight, and said plasticizer in an amount within the rangefrom about 0.5 to about 6% of the total composition weight.
 12. Thepharmaceutical composition of claim 10 wherein said methacrylic acidcopolymer is methacrylic acid copolymer.
 13. The pharmaceuticalcomposition of claim 8 wherein said plasticizer is triethyl citrate,triacetin, tributyl sebecate, or polyethylene glycol.
 14. Thepharmaceutical composition of claim 8 wherein said plasticizer isdiethyl phthalate.
 15. The pharmaceutical composition of claim 8 whereinsaid enteric coating includes methacrylic acid copolymer and diethylphthalate.
 16. The pharmaceutical composition of claim 5, furthercomprising an anti-adherent coating disposed on the exterior of saidenteric coating.
 17. The pharmaceutical composition of claim 16 whereinsaid anti-adherent coating is a hydrophobic material.
 18. Thepharmaceutical composition of claim 17 wherein the anti-adherent coatingis magnesium stearate or fumed silica.
 19. The pharmaceuticalcomposition of claim 18 wherein the anti-adherent coating is talc. 20.The pharmaceutical composition of claim 16 wherein said anti-adherent ispresent in an amount within the range from about 0.1% to about 4.0% ofthe total composition weight.
 21. The pharmaceutical composition ofclaim 5 wherein said disintegrant is cross-linked sodiumcarboxymethylcellulose, corn starch, or cross linkedpolyvinlpyrrolidone.
 22. The pharmaceutical composition of claim 5wherein said disintegrant is sodium starch glycolate.
 23. Thepharmaceutical composition of claim 5 wherein said binder is alkaline.24. The pharmaceutical composition of claim 23 wherein said binder issodium carboxymethylcellulose.
 25. The pharmaceutical composition ofclaim 5 wherein said medicament is pravastatin, erythromycin, digoxin,pancreatin, 2′, 3′-dideoxyadenosine, or 2′, 3′-dideoxycytosine.
 26. Thepharmaceutical composition of claim 5 wherein said medicament is 2′,3′-dideoxyinosine.
 27. The pharmaceutical composition of claim 26wherein said core comprises about 95% by weight 2′, 3′-dideoxyinosine,about 1% by weight sodium carboxymethylcellulose and about 4% by weightsodium starch glycolate.
 28. The pharmaceutical composition of claim 26wherein said composition is encapsulated in a capsule for oraladministration.
 29. The pharmaceutical composition of claim 28 whereinsaid capsule is filled with said composition in an amount equivalent toattain a dosage of ddI required for twice daily administration.
 30. Thepharmaceutical composition of claim 28 wherein said capsule is filledwith said composition in an amount equivalent to attain a dosage of ddIrequired for once daily administration.
 31. A pharmaceutical compositioncomprising: a) a dissolvable capsule; and b) the pharmaceuticalcomposition of claims 5, 16, or 27 which is encapsulated within saiddissolvable capsule.
 32. A process for preparing spheronized beadlets,comprising: a) mixing a granulation solvent, a medicament, optionally adisintegrant, and optionally a binder to form a wet mass; b) extrudingthe wet mass to form an extrudate; c) spheronizing the extrudate to formbeadlets; and d) while spheronizing, dusting the extrudate and theforming beadlets with a dry powder containing medicament, the optionaldisintegrant and the optional binder, which are in the same proportionsas contained in the wet mass, to form non-agglomerating beadlets; and e)drying the non-agglomerating beadlets to form said spheronized beadlets.33. A process for preparing a pharmaceutical composition of entericallycoated beadlets, comprising: a) mixing a granulation solvent, amedicament, optionally a disintegrant, and optionally a binder to form awet mass; b) extruding the wet mass to form an extrudate; c)spheronizing the extrudate to form beadlets; d) while spheronizing,dusting the extrudate and forming beadlets with a dry powder containingthe medicament, the optional disintegrant and the optional binder, whichare in the same proportions as contained in the wet mass, to formnon-agglomerating beadlets; e) drying the non-agglomerating beadlets toform dry beadlets; and f) forming an enteric coating on the drybeadlets, thereby forming the pharmaceutical composition of entericallycoated beadlets.
 34. The process of claim 32 wherein the proportions ofcomponents within the wet mass are between about 80% to about 100% byweight of medicament, between about 0% to about 10% by weight ofdisintegrant, and between about 0% to about 10% by weight of binder,thereby forming high potency beadlets.
 35. The process of claim 32wherein the medicament is an acid labile medicament.
 36. The process ofclaim 35 wherein the acid labile medicament is selected from the groupconsisting of 2′, 3′-dideoxyadenosine, 2′, 3′-dideoxycytosine,pravastatin, erythromycin, digoxin and pancreatin.
 37. The process ofclaim 35 wherein the acid labile medicament is 2′, 3′-dideoxyinosine.38. The process of claim 32 wherein the disintegrant is selected fromthe group consisting of cross-linked sodium carboxymethylcellulose, cornstarch and cross-linked polyvinylpyrrolidone.
 39. The process of claim32 wherein said disintegrant is sodium starch glycolate.
 40. The processof claim 32 wherein the binder is selected from the group consisting ofhydroxypropylmethylcellulose, potassium alginate, sodium alginate andpartially pregelatinized corn starch.
 41. The process of claim 32wherein said binder is sodium carboxymethylcellulose.
 42. The process ofclaim 32 wherein said granulation solvent is water.
 43. The process ofclaim 33 wherein the enteric coating is formed from a polymer and aplasticizer.
 44. The process of claim 43 wherein the plasticizer isselected from the group consisting of triethyl citrate, triacetin,tributyl sebecate and polyethylene glycol.
 45. The process of claim 43wherein said plasticizer is diethyl phthalate.
 46. The process of claim43 wherein the polymer is selected from the group consisting ofmethacrylic acid copolymer, hydroxypropylmethylcellulose phthalate,polyvinyl acetate phthalate and cellulose acetate phthalate.
 47. Theprocess of claim 46 wherein said enteric coating includes methacrylicacid copolymer and diethyl phthalate.
 48. The process of claim 46wherein said methacrylic acid polymer is methacrylic acid copolymer. 49.The process of claim 33, further comprising the step of coating theenterically coated beadlets with an anti-adherent to form anti-adherentcoated beadlets.
 50. The process of claim 49 wherein the anti-adherentis selected from the group consisting of magnesium stearate or fumedsilica.
 51. The process of claim 49 wherein said anti-adherent is talc.52. The process of claim 49, further comprising the step ofencapsulating the coated beadlets within a capsule.
 53. The process ofclaim 34 wherein a) the medicament is 2′, 3′-dideoxyinosine; b) thedisintegrant is sodium starch glycolate; and c) the binder is sodiumcarboxymethylcellulose.